Histamine is a biogenic amine with the following structural configuration: ##STR1##
Histamine is secreted by various types of cells, and it may become attached to receptors on the membranes of other cells. The attachment of histamines to histamine receptors can cause or aggravate a wide variety of physiological reactions, including vasodilation, bronchoconstriction, secretion of gastric acids, and skin hives [1]. The term "histamine" as used herein includes substituted forms of histamine, such as methyl histamine.
The effects of histamine may be mimicked by compounds that are referred to as agonists [2]. Histamine agonists include 2(2-pyridyl)ethylamine, dimaprit, and various substituted histamines, such as 4-methylhistamine. Histamine agonists mimic the effect of histamine by attaching to histamine receptors.
The effects of histamine may be blocked by compounds that are referred to as antagonists [3]. Histamine antagonists include diphenhydramine and cimetidine, which block various effects of histamine by attaching to histamine receptors without inducing the physiological effects caused by histamine. However, at high dosage levels, certain antagonists such as impromidine may cause agonistic effects on certain types of cells.
Histamine receptors are believed to be proteinous molecules with molecular weights in the range of 40,000 to 50,000 daltons. They are divided into at least two categories, designated as H1 receptors and H2 receptors [4]. Histamine will bind to either type of receptor. Certain antagonists such as diphenhydramine will bind to and consequently block H1 receptors to a much greater extent than they will block H2 receptors. Other antagonists, including cimetidine, will bind to H2 receptors to a much greater extent than they will block H1 receptors. It is believed that binding of histamine to H2 receptors plays an important role in the activation of gastric secretion. Therefore, H2 antagonists such as cimetidine are commonly used to treat ulcers by reducing gastric secretion [5]. It is believed that binding of histamine to H1 receptors plays an important role in skin hives and bronchioconstriction [6]. It is suspected that other categories of histamine receptors exist, which are not blocked by H1 blockers or by H2 blockers. For convenience, such receptors are referred to herein as H3 receptors.
When a histamine, histamine agonist, or histamine antagonist molecule binds to a histamine receptor, the reaction is referred to herein as specific binding. By comparison, if histamine (which is a somewhat reactive molecule) clings or binds to some other part of a cell, a test tube, a filter, or any other surface, such a reaction is referred to herein as non-specific binding.
Histamine blockers, as used herein, is a generic term comprising histamine agonists, histamine antagonists, and other molecules which are capable of specific binding with a histamine receptor, thereby preventing a histamine molecule from specifically binding to the blocked receptor. By comparison, antihistamines which react with histamine, rather than with histamine receptors are not regarded herein as histamine blockers. A histamine blocker which binds to H1 receptors with greater affinity than it binds to H2 receptors is referred to as an "H1 blocker;" for example, diphenhydramine (which is commercially available under the trademark Benadryl (Parke-Davis, Morris Plains, NJ) is an H1 blocker. Alternately, an H2 blocker such as cimetidine (which is commercially available under the trademark Tagamet (Smith Kline and French Co., Philadelphia, PA)) binds preferentially to H2 receptors.
Certain diseases are characterized by, and may be caused or aggravated by, imbalances in H1 and H2 receptor density on lymphocytes and other types of human cells. Such diseases include atopic disease [7], neoplastic disease [8], histiocytosis-X [9], autoimmune disease [10], and other diseases [11]. In order to diagnose, study, and treat such diseases it is useful to determine the existence, concentration, and biochemical affinity of H1 and H2 receptors on various types of human cells.
Although it has been recognized since 1910 that histamine causes a variety of physiological reactions, research on histamine receptors has proceeded slowly. The majority of histamine research involved detection of physiological responses, such as muscle contraction or vasodilation, which occur when tissue is contacted with histamine [12]. Some research involved the biochemical production of certain molecules, such as cyclic adenosine monophosphate (cAMP) by cells contacted with histamine [13]. In 1966, it was recognized that mepyramine, when incubated with tissue, blocked certain types of physiological responses but not other types of responses when the tissue was subsequently contacted with histamine. Based upon that result, scientists speculated that at least two types of cell membrane receptors existed, designated as H1 and non-H1 receptors [14]. In 1972, it was discovered that burimamide blocked several responses that differed from the responses blocked by mepyramine; this led to the designation of H2 receptors [15]. However, most of the research since 1972 has continued to focus upon physiological responses or cAMP stimulation [ 16]. There has been very little work to analyze, through biochemical binding reactions, the presence and concentration of H1 and H2 receptors on membranes [17]. Such work has suffered from serious drawbacks which hindered or prevented accurate and convenient analyses of histamine receptors.